Noncirrhotic portal hypertension in the pediatric population

Watch a video presentation of this article

Answer questions and earn CME

Abbreviations

CHF

congenital hepatic fibrosis

CT

computed tomography

EHPVO

extrahepatic portal vein obstruction

MR

magnetic resonance

NAFLD

nonalcoholic fatty liver disease

NCPH

noncirrhotic portal hypertension

NRH

nodular regenerative hyperplasia

SOS

sinusoidal obstruction syndrome.

Noncirrhotic portal hypertension (NCPH) describes a group of disorders in which portal hypertension develops despite absence of cirrhosis. In pediatrics, the most common cause of NCPH is extrahepatic portal vein obstruction (EHPVO), which has been reported to be responsible for up to one‐third of esophageal varices in children.1 Other causes of NCPH in children include congenital hepatic fibrosis (CHF), nodular regenerative hyperplasia (NRH), nonalcoholic fatty liver disease (NAFLD), sinusoidal obstruction syndrome (SOS), and rarely metabolic diseases (Gaucher's and Zellweger syndrome), schistosomiasis, and hepatoportal sclerosis.

Extrahepatic Portal Vein Obstruction

EHPVO occurs when forward hepatopedal flow of blood from the splenic and superior mesenteric veins through the prehepatic portion of the portal vein is hindered by a physical obstruction. Although EHPVO is relatively uncommon in Western countries, in the developing world it is a major cause of pediatric portal hypertension (54% of cases) and is responsible for the majority of pediatric upper gastrointestinal bleeding (68%‐84%).2 In children, EHPVO can either be idiopathic or be the result of congenital abnormalities, prothrombotic states, autoimmune systemic disease, vasculitis, local inflammatory conditions, portal vein injury, or occur post–liver transplantation (Table 1).2 There is a bimodal age of presentation during childhood with patients affected by umbilical sepsis or omphalitis presenting in the first few years of life and those affected by intra‐abdominal infection, coagulation abnormalities, or idiopathic presenting later in childhood or adolescence.2 Children with EHPVO may present with signs of portal hypertension (thrombocytopenia, anemia, splenomegaly, gastrointestinal bleeding), portal biliopathy (jaundice, elevated alkaline phosphatase, elevated gamma‐glutamyl transpeptidase), growth failure, or minimal hepatic encephalopathy. With prolonged duration of disease, liver dysfunction, including hypoalbuminemia and ascites, may develop.

Table 1.

Causes of Extrahepatic Portal Vein Obstruction in Children

Etiological Factor
Hematologic
Factor V Leiden mutation
Prothrombin gene mutation
Methyltetrahydrofolate reductase (MTHFR) gene mutation
Hyperhomocysteinemia
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
Antiphopholipid syndrome
Paroxysmal nocturnal hemoglobinuria
Local inflammatory conditions
Abscess
Abdominal sepsis
Inflammatory bowel disease
Pancreatitis
Portal vein injury
Trauma
Abdominal surgery
Umbilical vein catheterization or sepsis
Liver transplantation
Idiopathic

EHPVO can be diagnosed by Doppler ultrasound with 95% sensitivity and specificity.3 The portal vein is transformed into a cavernoma, an irregular vascular structure of thin veins visualized near the hepatic hilum which can result in elevated portal resistance and compression of the biliary system. Often, a computed tomography scan (CT) or magnetic resonance (MR) angiography/portography can be useful in further defining the vascular connections (Fig. 1). Occasionally, a large portal collateral vessel coursing through the porta hepatis may be mistaken for a portal vein and the diagnosis missed. Bleeding varices can usually be managed by endoscopic band ligation or sclerotherapy. There are no data supporting the use of nonselective beta‐blockers as primary or secondary prophylaxis in this condition. Children with EHPVO are commonly evaluated for a meso‐Rex bypass, a surgical procedure that connects the superior mesenteric vein to the left portal vein (if present) using an internal jugular patch. This procedure bypasses the obstruction and restores normal portal flow into the liver. There is evidence that the meso‐Rex bypass not only prevents gastrointestinal bleeding from portal hypertension, but also improves coagulopathy,4 somatic growth,5 portal biliopathy,6 hypersplenism, and neurocognitive defects,7 in addition to preventing liver synthetic dysfunction in adulthood.8 If the meso‐Rex bypass cannot be performed due to an unsatisfactory intrahepatic portal vein, a distal splenorenal shunt should be considered if bleeding cannot be controlled by variceal sclerosis or band ligation.

Figure 1.

CT scan of extrahepatic portal vein obstruction. CT abdomen of a 6‐year‐old child with extrahepatic portal vein thrombosis. Portal vein obstruction is observed (thick arrow) with poor visualization of the portal veins after the main portal vein bifurcation in the porta hepatis. Secondary signs of portal hypertension including marked splenomegaly and collateralization are also demonstrated (thin arrow).

Congenital Hepatic Fibrosis

CHF is an autosomal recessive ciliopathy caused by premature arrest in the remodeling of the embryonic ductal plate resulting in malformation of the bile ducts. The majority of cases (at least 60%‐70% of cases) are associated with autosomal recessive polycystic kidney disease (ARPKD) in which a mutation in the PKHD1 gene causes biliary abnormalities (ectatic intrahepatic ducts and, not uncommonly, fusiform choledochal cyst), and fusiform dilation of the renal collecting ducts. The remaining cases are either isolated, part of another fibrocystic syndrome (such as autosomal dominant PKD), or associated with Caroli syndrome (which is also associated with mutations in PKHD1) in which cystic dilation of intrahepatic bile ducts are present.9 Most patients with CHF present in late childhood or early adulthood with signs of portal hypertension (splenomegaly/hypersplenism or upper gastrointestinal hemorrhage) and/or cholestasis and cholangitis.10 Unlike other causes of portal hypertension, patients with CHF most often have preserved liver synthetic function. Diagnosis is suggested on ultrasound, CT, or MR where hepatomegaly, splenomegaly, biliary dilation, and/or hepatic and renal cysts can be seen. Mutation analysis can be performed in patients in whom ARPKD is suspected. Liver biopsy is not necessary for diagnosis, but when performed will reveal normal hepatocytes separated by broad dense septa of fibrous tissue with abnormal appearing ectatic bile ducts. Unlike cirrhotic liver, there is no nodular regeneration or inflammation (Fig. 2). Morbidity and mortality are generally related to undernutrition, cholangitis (particularly in Caroli's syndrome), hypersplenism, renal failure, and gastrointestinal bleeding. Therapy is directed to nutritional support, antibiotics for cholangitis or infected biliary cysts, and management of esophageal and gastric varices. When endoscopic therapy is not successful in preventing rebleeding, distal splenorenal or portocaval shunting should be considered, because the development of synthetic liver failure is unusual. Transjugular intrahepatic portosystemic shunting (TIPS) is generally contraindicated because of the risk of puncturing dilated bile ducts or cysts, the risk of contrast‐induced kidney injury in people with preexisting kidney disease, and the 10% risk/year of occlusion of the shunt. In severe cases of CHF lobectomy, hepatojejunostomy or transplantation (liver or combined liver/kidney) can be considered. Only 4% of patients with CHF ultimately require liver transplantation.11 Genetic counseling for the family is essential.

Figure 2.

Histopathology of noncirrhotic portal hypertension in CHF by light microscopy. Liver explant from a 13‐year‐old child with congenital hepatic fibrosis secondary to autosomal recessive polycystic kidney disease. (A) The noncystic portions of the liver show bridging fibrosis as highlighted by the trichrome stain (large thick arrow), with extensive, almost circumferential bile duct proliferation. (B) Hepatic parenchyma is characterized by focal large cysts lined by bland biliary epithelium (thin arrow) with a rim of vascular tissue embedded in fibrosis. Magnification at (A) 4× and (B) 10×.

Nonalcoholic Fatty Liver Disease

As the population of obese children continues to increase, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease in children. In one pediatric study, 60% of patients with NAFLD had fibrosis and 3% had cirrhosis.12 Even before true fibrosis and cirrhosis develop, steatosis alone may result in increased risk for hepatocyte ischemia‐reperfusion injury. This problem is well known in the liver transplant population where recipients of grafts with high steatosis are at greater risk for primary nonfunction and other complications. Reduction of sinusoidal flow and reduction of intrahepatic portal flow in livers with ischemia‐reperfusion injury may induce NCPH.

Nodular regenerative hyperplasia

Nodular regenerative hyperplasia (NRH) is a rare disorder in which hepatocytes undergo hyperplastic transformation and form small regenerative nodules without surrounding fibrosis, frequently in response to microvascular changes in the liver. NRH can occur in response to drugs and toxins (eg, azathioprine, 6‐mercaptopurine, 6‐thioguanine), after liver transplantation,13 as a result of portal venopathy/injury, or in association with autoimmune, inflammatory, or neoplastic disorders. The majority of patients with NRH are asymptomatic; however, there is a subset of patients who present with portal hypertension. Most pediatric patients have slow progression of portal hypertension except for the group of children who received 6‐thioguanine for treatment of leukemia or inflammatory bowel disease in past years.

Sinusoidal Obstruction Syndrome

Sinusoidal obstruction syndrome (SOS) is a nonthrombotic obstruction of the hepatic sinusoids, formerly called hepatic veno‐occlusive disease (VOD). Injury and detachment of the sinusoidal epithelial cells allows for red cell extravasation into the space of Disse, promoting increased sinusoidal resistance and subsequent severe portal hypertension. SOS occurs most frequently following high‐dose myeloablative therapy for stem cell transplant using cyclophosphamide, busulfan, and total body irradiation. Patients with SOS present with acute tender hepatomegaly, jaundice, and acute weight gain secondary to ascites within days to weeks of stem cell transplant. Ultrasound may show reversal of flow in the portal vein, decreased hepatic venous flow, thickening of the gallbladder wall, or increased resistive indices in the hepatic artery. The gold standard for diagnosis is a wedged hepatic venous pressure gradient greater than 10, although this is generally unnecessary. Ursodeoxycholic acid therapy after myeloablative therapy for stem cell transplant is routinely provided to prevent SOS. Treatment of SOS includes avoidance of fluid overload, initiation of ursodeoxycholic acid, and consideration of defibrotide14 or other fibrinolytic promoting medications. Seventy percent of patients with SOS recover with supportive care15; however, liver failure may develop in nonresponders to supportive care. TIPS procedure is generally not helpful in this condition.

Summary

NCPH is an uncommon cause of portal hypertension in children; however, it must be considered in cases where there is evidence of portal hypertension without evidence of cirrhosis or liver synthetic dysfunction. EHPVO is the most common cause in children. In general, NCPH has a good long‐term prognosis if the complications of portal hypertension can be controlled with medications or interventional procedures. However, in rare cases NCPH can result in portal biliopathy, significant neurocognitive dysfunction, or liver dysfunction in children.